Bismuth compounds

ABSTRACT

The use in diagnostic imaging, in particular X-ray, MRI, ultrasound and scintigraphy, of contrast agents comprising bismuth clusters and/or organic bismuth compounds, and contrast media containing such bismuth compounds. The bismuth compounds are also useful in therapy, in particular as antimicrobial agents and antiulcer agents. Novel bismuth compounds are also disclosed.

This is a continuation of U.S. Ser. No. 09/369,694, filed Aug. 6, 1999,which is a continuation of U.S. Ser. No 08/875,305, filed Jul. 23, 1997,now U.S. Pat. No. 6,117,412, which is a continuation of InternationPatent application No. PCT/GB96/00183, with an international filing dataof Jan. 26, 1996, now WO 96/22994, which is a continuation-in-part ofU.S. Ser. No. 08/486,225, filed Jun. 7, 1995, issued on Oct. 6, 1998 asU.S. Pat. No. 5,817,289, which all claim priority from Great Britain9501560.8, filed Jan. 26, 1995.

The present invention relates to the use in diagnostic imaging, inparticular X-ray, MRI, ultrasound and scintigrapny, of contrast agentscomprising bismuth clusters and/or organic bismuth compounds, and tocontrast media containing such bismuth compounds. Another aspect of thepresent invention is the use of the bismuth compounds in therapy, inparticular as antiulcer agents.

All diagnostic imaging is based on the achievement of different signallevels from different structures within the body. Thus in X-ray imaging,for example, for a given body structure to be visible in the image theX-ray attenuation by that structure must differ from that of thesurrounding tissues. The difference in signal between the body structureand its surroundings is frequently termed contrast and much effort hasbeen devoted to means of enhancing contrast in diagnostic imaging sincethe greater the contrast between a body structure and its surroundingsthe higher the quality of the images and the greater their value to thephysician performing the diagnosis. Moreover, the greater the contrastthe smaller the body structures that may be visualized in the imagingprocedure, i.e. increased contrast can lead to increased spatialresolution.

The diagnostic quality of images is strongly dependent on the inherentnoise level in the imaging procedure—the ratio of the contrast level tothe noise level can thus be seen to represent an effective diagnosticquality factor for diagnostic images.

Achieving improvement in such a diagnostic quality factor has long beenand still remains an important goal. In techniques such as X-ray andultrasound, one approach to improve the diagnostic quality factor hasbeen to introduce contrast enhancing materials, contrast agents, intothe body region being imaged.

Thus in X-ray, for instance, early examples of contrast agents wereinsoluble inorganic barium salts which enhanced X-ray attenuation in thebody zones into which they distributed. More recently the field of X-raycontrast agents has been dominated by soluble iodine containingcompounds such as those markedet by Nycomed AS under the trade namesOmnipaque® and Visipaue®.

Much recent work on X-ray contrast agents has concentrated onaminopolycarboxylic acid (APCA) chelates of heavy metal ions and,recognising that effective imaging of many body sites requireslocalization at the body sites in question of relatively highconcentrations of the metal ions, there have been suggestions thatpolychelants, that is substances possessing more than one separatechelant moiety, might be used to achieve this.

Various bismuth compounds have been suggested in the prior art as X-rayabsorbing agents. Other prior art documents focus on the use of metalchelates in diagnostic imaging, mainly in MRI. In addition, bismuthcompounds have a long history in therapeutic medicine specially intreatment of gastrointestinal diseases such as ulcers. Althoughantiulcer agents such as the H₂-antagonists cimetidine and ranitidine,and more recently proton pump inhibitors such as omeprazole, have beendeveloped, there is still medical use of bismuth compounds in ulcertreatment.

The most frequently used bismuth compounds as gastrointestinal drugstoday are bismuth subnitrate and bismuth subsalicylate. Bismuthsubnitrate or bismuth hydroxide nitrate oxide (Bi₅O(OH)₉(NO₃)₄ isprepared by hydrolysis of bismuth nitrate and is practically insoluablein water. It is usually used as a suspension (milk of bismuth). Bismuthsubnitrate is also used topically in lotions and ointments. Bismuthsubsalicylate or basic bismuth salicylate (C₇H⁵BiO₄) is also practicallyinsoluble in water and is administered as a suspension or in the form oftablets. Products containing bismuth subsalicylate are used againstindigestion, nausea and diarrhea. As an antidiarmheal agent it showsgood activity against Salmonella with less activity versus E. coli.

Several bismuth compounds are known to be biologically active and havebeen suggested as active ingredients in various drug formulations.Organobismuth compounds can be used as antibacterial agents, for exampleagainst infections caused by highly resistant gram-negative bacteria(U.S. Pat. No. 3,466,366 of M&T Chem Inc); a protein-type bismuthcomplex is suggested for treatment of inflammation and infections in thegastrointestinal system in U.S. Pat. No. 4,153,685 (Schering Corp);bismuthyl prostanoate derivatives for ulcer control are suggested in BE809388 (Aries R); phenylbismuth bis(2-pyridinethiol) 1-oxide as anantibacterial and antifungal agent is disclosed in U.S. Pat. No.3,824,307 (Procter & Gamble Co); an antiinflammatory and antiulcerbismuth composition containing a mixture of trivalent bismuth,water-soluble protein, an organic acid anion and an alkali in ZA 8107456(Schering Corp); bismuth subsalicylate in combination with other agentsin a synergistic formulation for diarrhoea treatment in U.S. Pat. No.4,588,589 (Richardson Vicks); treatment of non-ulcer dyspepsiaassociated with Campylobacter pyloridis infection with bismuth saltssuch as tripotassium dicitrato-bismuthate in WO 89/03219 (Borody T. J.);organo-bismuth compounds useful as anti-coccidium agents for poultry,and as insecticides in J63225391 (Nitto Kasei and Shionogi);pharmaceutical compositions for treatment of gastrointestinal disordersassociated with Campylobacter pylori infections comprising apharmaceutically acceptable bismuth compound and first and secondantibiotic or antimicrobial agents in EP 439453 (Capability Services etal.); salts formed between rantidine and bismuth carboxylic acidcomplexes for treatment of gastrointestinal disorders in U.S. Pat. No.5,008,256 (Glaxo); further salts formed between an H₂-receptorantagonist and a complex of bismuth with a carboxylic acid with activityagainst gastrointestinal conditions and aginst Campylobacter pylori inU.S. Pat. No. 5,273,984 (Glaxo); a suspension for oral administrationcomprising a bismuth containing pharmaceutical agent, benzoic acid andsorbic acid, polymer and water for use against various gastrointestinaldisorders in U.S. Pat. No. 5,013,560 (Procter & Gamble); furanderivatives with bismuth carboxylic acid complexes for treatment ofvarious gastrointestinal disorders including activity againstHeliobacter pylori infections in WO 92/01457 (Evans B. K. et al.); saltsof ranitidine with a bismuth carboxylate complex and alkali salt fortreatment of various gastrointestinal disorders in GB 2248185 (Glaxo);and ranitidine bismuth citrate and non-steroidal anti-inflammatory drugsfor the treatment of inflammation diseases in GB 2262036 (Glaxo).

Finally, WO 95/06053 discloses certain substituted triphenyl bismuthcompounds as X-ray contrast agents.

We have now found that certain bismuth compounds give particularlyeffective contrast enhancement when used as contrast agents. Some ofthese compounds also can be used in the treatment of variousgastrointestinal disorders.

Thus, one aspect of this invention is a diagnostic imaging contrastmedium comprising a covalent non-cluster type bismuth compound. Suchmedium may be used for contrast enhancement in diagnostic imaging, inparticular x-ray, MRI, ultrasound imaging and scintigraphy.

For X-ray or ultrasound imaging it is preferred that the compoundscomprise two or more heavy atoms where at least one of the heavy atomsis bismuth. For the sake of clarity, the word “heavy atom” means abromine atom or an atom with atomic number higher than 49.

For MRI the compounds would comprises bismuth and one or more MR activeatoms. For the sake of clarity, the words “MR active atom” means an atomthat directly or indirectly affects the MR signal. Typical MR activeatoms include for example manganese, gadolinium, dysprosium, iron andfluorine.

The invention provides for example diagnostic imaging contrast mediacomprising a physiologically tolerable molecule of anyu of formulaeI-IV,

where the groups R₁-R₅ may be the same or different and are defined asany croup forming a hydrolyticaliy stable bond to bismuth. Typical R₁₋₅groups are preferrably aryl groups substituted with one or more heavyatoms, preferably Bi and I. X is O, S or NR₆ where R₆ is lower alkyl,for example C₁₋₄-alkyl, substituted lower alky, or an aryl group.

Viewed from another aspect, the invention provides a diagnostic imagingcontrast medium comprising a non-covalent non-cluster type bismuthcompound, with the proviso that the bismuth compound contains at leastone further heavy atom.

The further heavy atom in such non-covalent non-cluster type compoundsmay be covalently or non-covalently bonded and may, for example, be aniodine atom. The compound may contain more than one non-covalentlybonded bismuth atom, for example 2 or 3 such atoms or even 10 or moresuch atoms.

Viewed from another aspect, the invention provides a diagnostic imagingcontrast medium comprising a physiologically tolerable multinuclearbismuth complex of formula V,

(M_(m)B_(n)A_(p))_(x)L_(y)  (V)

where M_(m)B_(n)A_(p) is a multinuclear entity where each M which may bethe same or different is a contrast enhancing heavy metal atom and atleast one M is Bi (and preferably each M is Bi) and each M is covalentlybonded to at least one atom B when n is non-zero; each B which may bethe same or different is a non-metal bridging atom covalently bonded toat least two M atoms and optionally to further atoms; each A which maybe the same or different is a non-metal non-bridging atom covalentlybonded to an M atom; each L which may be the same or different is aligand co-ordinately bonded to at least one Bi atom; m is a positiveinteger of value 2 or greater; n, p and y are independently zero orpositive integers provided that n and p are not simultaneously zero; xis a positive integer; or a physiologically tolerable salt thereof,together with at least one pharmaceutical excipient.

Viewed from another aspect, the invention also provides the use ofbismuth compounds as defined above for the manufacture of contrast mediafor use in imaging of the human or non-human body.

Viewed from a still further aspect, the invention provides a method ofgenerating an image of a human or non-human animal, preferablymammalian, body which method comprises administering to said body aphysiologically tolerable contrast enhancing amount of a bismuthcompound as defined above and generating an image of at least part ofsaid body into which said agent distributes, e.g. by X-ray, MRI orultrasound imaging or scintigraphy.

Viewed from a still further aspect the invention also provides adiagnostic imaging contrast medium comprising a bismuth compound asdefined above together with at least one sterile pharmaceutical carrieror excipient.

Viewed from a still further aspect the invention also provides the useof the cluster and covalent non-cluster bismuth compounds as definedabove for the manufacture of therapeutic agents for treatment ofgastrointestinal disorders, for example caused by Heliobantpr pylori.

Viewed from a still further aspect, the invention provides a method oftreating a gastrointestinal disorder, for example caused by Heliobacterpylori, of a human or non-human animal, preferably mammalian, body whichmethod comprises administering to said body a physiologically tolerabledose of a cluster or covalent non-cluscer bismuth compound as definedabove.

The bismuth compounds defined above have particular potential ascontrast agents since the compounds have a relative high concentrationof heavy elements including bismuth. The use of these compounds enablesa high ratio of contrast enhancing atom to overall structure volume tobe achieved. Thus by increasing the relative content of contrastenhancing atoms in this way the total cuantity of the contrast agentnecessary in order to achieve the same contrast effect may be reducedand thus problems associated with contrast agent solubility or toxicityor osmolality or with contrast medium viscosity may also be reduced.

As mentioned above, it is preferred that the bismuth compounds of theinvention comprise two or more contrast enhancing atoms. Both thecovalent bismuth molecules and multinuclear cluster chelates alsocontain further atoms which may have little or no contrast enhancingeffect but which may for example function as bridging atoms binding thecontrast enhancing atoms together in a cluster (See WO 92/17215 forfurther examples of these types of structures). Other non-contrastactive atoms in the contrast agent function for example asdetoxification groups, as solubilizing groups, in groups for targetingof the bismuth atom and the other contrast-active atoms to the area ofinterest, or the non-contrast active atoms help to stabilize thecovalent molecule or chelate against hydrolysis and metabolism.

The bismuth compounds described above may, as pointed out above, be usedin various modalities in medical imaging and in certain specifictherapeutic fields. Some bismuth compounds are active in more than onemodality. The choice of modality should be carefully taken intoconsideration in design of the agent. For example if the agent isintended for use in MRI, MR active elements such as fluorine and/orparamagnetic elements such as manganese or gadolinium preferably formpart of the molecule.

However, one of the most interesting applications of these bismuthcontaining compounds is in X-ray imaging. For use as an X-ray contrastagent, it is preferred that the compounds contain bismuth and at leastone more heavy atom. The preferred bismuth compounds may in addition tobismuth contain atoms such as bromine, iodine, lanthanides, transitionmetals, or other metal atoms. Examples include Gd, Ce, Sr, Y, Zr, Ru,Rh, In, Ta, Nb, Dy, Hf, W, I, Mo, Re, Os, Pb, Ba, Ga, Sn, Ha and Tl.Bismuth compounds containing several bismuth and/or several iodine atomsare most preferred. The choice of heavy atom and the number of heavyatoms in each unit are determined by a variety of factors including thetoxicity of the overall molecule or cluster complex, the in vitro and invivo (shelf life) stability of the unit and the X-ray absorptioncharacteristics of the heavy atom. In this regard it should be notedthat while the X-ray absorbtion cross section for atoms generallyincreases with increasing atomic number, the absorption cross section isitself dependent on the X-ray wavelength and increases with increasingphoton energy until slighthly above a value termed the K-edge whereafterattenuation decreases. Thus there are photon energy ranges for which oneelement is a better X-ray attenuator than a second even though outsidethese ranges the second element may be the better attenuator.Consequently the bismuth compounds according to the invention will eachhave optimum photon energy ranges making them particularly suitable foroperation with X-ray imaging apparatus utilizing X-rays having suchphoton energy ranges. However, by choosing bismuth compounds containingatoms of more than one heavy element one may create X-ray contrastagents having optimal performance in more than one photon energy band orover a broader band. The compounds used according to the presentinvention are thus particular attractive since they can be selected soas to match their X-ray attenuation profiles with the X-ray emissionprofiles of particular X-ray sources—in effect the invention provides“tunable” X-ray contrast media. From an efficacy point of view, bismuthand uranium are the heavy atoms with the highest efficacy per atom inall X-ray modalities (CT, plain X-ray and DSA).

In formula I-IV above, R₁-R₅ may be the same or different and may be anygroup forming a hydrolytically stable bond to bismuth. Typical R₁-R₅groups can for example be aryl groups, optionally substituted with oneor more heavy atoms such as Bi and I. For extracellular X-ray contrastagents the R₁₋₅ groups are usually substituted with one or more(preferably more) hydrophilic groups. Such compounds should in generalhave a low charge or preferably no charge.

The bond from bismuth to one of the R₁₋₅ groups may for example be ofthe following types: Bi—C, Bi—O, Bi—S and Bi—N. Some of these bonds aremore stable than others and it is known in the literature on thechemistry of bismuth that the stability of the bismuth molecule is verydependent on the chemical nature of this bond and the substituents (seefor example Chapter 28 in G. Wilkinson (ed) Comprehensive CoordinationChemistry; Gmelin Handbuch der Anorganischen Chemie Volume 47; L. D.Freedman and G. O. Doak in Chem. Rev (1982) 82 15-57; Methoden derOrganischen Chemie (Houben-Weyl) Volume XIII/8; ComprehensiveOrganometallic Chemistry, Chapter 13; Kirk-Othmer: Encyclopedia ofChemical Technology Volume 3 p 921-936).

Some trialkylbismuth compounds are known to be very hydrolyticallyunstable, however, we have shown that triarylbismuth compounds aresurprisingly stable against hydrolysis: triphenylbismuth dissolved inaqueous (25%) tetrahydrofuran is stable under reflux for many days. Whenthe R₁₋₅-groups form Bi—C bonds, aryl grou7ps are generally preferred.At least one of the R₁₋₅-groups should be an aryl group or substitutedaryl group. The term “aryl group” here means any aromatic hydrocarbonring system or aromatic heterocyclic system. Typical ring systemsinclude for example benzene, naphthalene, indene, fluorene, phenalene,phenanthrene, anthracene, fluoranthene, acephenanthrylene,aceanthrylene, triphenylene, pyrene, chrysene, naphthacene, pleiadene,picene, perylene, pentaphene, pentacene, tetraphenylene, hexaphene,hexacene, rubicene, coronene, trinaphthylene, heptaphene, rubicene,coronene, heptacene, pyranthrene, ovalene, furan, thiophene,thianthrene, pyran, isobenzofuran, chromene, xanthene, phenoxathin,pyrrole, imidazole, pyrazole, isothiazole, isoxazole, pyridine,pyrazine, pyrimidine, pyradizine, indolizine, isoindole, indole,indazole, purine, quinolizine, isocaunoline, quinoline, phtalazine,naphyhyridine, quinoxaline, quinazoline, cinnoline, pteridine,carbazole, β-carboline, phenanthridine, acridine, permidine,phenanthroline, phenazine, phenarsazine, phenothiazine, furazan,phenoxazine, isochroman, chroman, indoline and iso-indoline.

Possible alkyl groups include both substituted or unsubstituted lowerand higher alkyl, alkoxy, polyalkoxy and alkylaryl groups, or any othergroups.

The R₁₋₅ groups may be substituted with contrast active elements orcontrast active groups and other non-contrast active elements or groups.Typical contrast active elements are listed above. The most preferredcontrast active elements for X-ray imaging are iodine and bismuth. Othersubstituents include fluorine, chlorine, bromine, alkyl, alkoxy,substituted alkyl for example hyd-oxyalkyl or polyhydroxyalkyl,substituted alkoxy for example hydroxyalkoxy or polyhydroxyaloxy, amidesincluding substituted amides such as —NAcR₆ and CONR₇R₈ where Ac is anacyl group and R₆R₈ which may be the same or different represent loweralkyl, C₁₋₄-hydroxyalkyl, carboxy- or amino-C₁₋₄-alkyl groups ortogether both R₇ and R₈ represent a cyclic croup such as—CH₂CH₂NR₉CH₂CH₂— where R₉ for example, is a C₁₋₄ alkyl group optionallysubstituted by hydroxyl, carbonyl, aryl or amino groups.

Particularly conveniently, the multinuclear bismuth complexes arepresented as their chelate complexes containing EDTA or other APCAs.Such chelate complexes are remarkably stable with regard to release ofthe heavy metal ions. It is particularly preferred that the electricalcharge carried by the completing moieties should substantially if notcompletely balance that carried by the complexed entity; for APCAchelants this may easily be achieved for example by omission,replacement or deactivation (e.g. by ester or amide formation) of one ormore of the carboxyl moieties.

Many suitable chelants are widely known or have been described in theliterature, especially literature relating to heavy metal detoxificationagents, bifunctional chelants and chelate-based contrast agents, e.g.those described in WO-A-89/00557 (Berg) and the documents mentionedtherein and in the search report appended thereto, U.S. Pat. No.4,647,447 (Gries), U.S. Pat. No. 4,826,673(Dean), EP-A-230893 (Felder),EP-A-217577 (Frincke), U.S. Pat. No. 4,652,519 (Warshawsky), U.S. Pat.No. 4,687,659 (Quay), and numerous other recent patent publications ofNycomed AS, Salutar Inc, Schering AG, Squibb, Bracco, Mallinckrodt, Dowand Guerbet.

While polyamines, especially linear or cyclic polyamines, such asethylenediamine, 1,4,7-triazacyclononane and cyclen, can be used aschelants, in general APCAs are preferred, particularly DTPA, EDTA andderivatives thereof and other cyclic and non-cyclic APCAs as defined inWO-A-89/00557.

Examples of suitable chelnts include compounds of formulae;

and the phosphorus analogues of these nitrogen-donor based ligands.

Chelants such as NTA, IDA, EDTA, HEDTA, DTPA, DTPA-BMA, HEDDA, TTDA,EDTA-BMA, TBEDDA, MEEDDA, TTHA, EDDA, EHPG, PDTA, CHDTA, HPDTA andtriazacyclononane monoacetic acid, especially PDTA and EDTA, are ofparticular interest.

Particularly preferred chelants include cyclen, EDTA, DTPA, DOTA, DO3A,HP-DO3A, the 6-oxa and 6-thia analogues of DTPA and amides thereof, e.g.DTPA-BMA and DTPA-BMO(6-carboxymethyl-3,9-bis(morpholinocarbonyl-methyl)-3,6,9-triazaundecanedioic acid—the Gd(III) chelate of which is sometimesreferred to as gadopenamide).

Where the chelant is to be attached to a macromolecule, this mayconveniently be any tissue, organ or cell targeting macromolecule, forexample a biomolecule such as a protein, an antibody or antibodyfragment, or alternatively it may be a biologically relatively inertmaterial such as a polysaccharide or poly-sugar alcohol, e.g. dextran orstarch. Such macromolecules are discussed extensively in the recentliterature relating to contrast agents.

The bismuth compounds used according to the invention may be ionic or,more preferably, may carry no net charge; most preferably the compoundis non-ionic. Moreover they may be water-soluable or, less preferably,water-insoluable. Compounds with low solubility in water could be usedas X-ray contrast agents for liver, spleen, lymphatic blood pool andgastrointestinal system imaging. Water-soluble macromolecular bismuthcompounds (mw>20000) could be used as blood pool X-ray contrast agents.Any necessary counter-ions should of course most preferably also bephysiologically tolerable.

The range of physiologically acceptable counterions for therapeuticallyactive bismuth agents is of course well known to pharmacologists.

Suitable counter-ions include for example protons, alkali and alkalineearth metal ions, e.g. sodium, calcium and magnesium and zinc, ammoniumand organic cations (e.g. organic amine cations, iodinated organic aminecations, cuarternary ammonium, pyridinium, meglumine, alkylammonium,polyhydroxy-alkylammonium, baser protonated amino acids etc.),transition metal complex cations and organometallic cations.

Suitable counter-ions also include for example halide (e.g. choride,bromide, iodide and I₃ ⁻).

The invention also provides novel covalent non-cluster type bismuthcompounds, with the proviso that when the bismuth compound is atriphenyl bismuth compound it contains at least one further heavy atom,or at least one of the phenyl groups is substituted in at least four ofits ortho, meta and para positions and the molecule as a whole containsat least one hydroxy group or carboxyl group. Preferably the compoundsalso contain at least one further covalently bonded bismuth atom or atleast one covalently bonded iodine atom.

This invention thus provides new bismuth compounds of formula I whichmay be represented as follows:

R_(A-K) in formulae (Ia)-(Ih) can be the same or different. TypicalR_(A-K) groups can for example be —COOH, —NHCOCH₃, —N (Me)COCH₃,—CONHCH₃, —CONHCH₂Ch₂OH, —CONHCH₂CONHCH₃, NHCOCHOHCH₃, —NHCOCH₂OCH₃,—CONHCH₂CHOHCH₃OH, —CON(Me)CH₂CHOHCH₂OH, —CONHCH(CH₂CH₂OH)₂,—CONHCH(CH₂OH)₂ CHOHCH₂OH, —CONHCH(CH₂OH).CHOH. CHOH.CH₂OH, —OCH₂CH₂OH,—NHCOCH₂OH, —CH₂OH and N(COCH₂OH) (CH₂CH₂OH).

This invention also provides new bismuth compounds of formula II whichmay be represented as follows:

R_(A)-R_(D) in formulae (Ila)-(IIc) can be the same or diferent andtypical R_(A-D) groups are listed above. BG can be any bridging group.In the compounds of the invention, the linker group BG is conveniently a1, 2 or 3 membered chain comprising carbon, nitrogen, oxygen or sulphuratoms, e.g. a O, S, N or C one atom chain, a NN, NC, NS, CC or CO twoatom chain, or a NCN, OCN, CNC, OCO, NSN, CSN, COC, OCC or CCC threeatom chain, for example:

an oxygen atom or a group NR¹, CO, SO₂ or CR₂ ¹;

a group COCO, CONR¹, COCR₂ ¹, SOCR₂ ¹, SO₂NR¹, CR₂ ¹CR₂ ¹,

CR₂ ¹NR¹ or CR¹ ₂O;

a group NR¹CONR¹, OCONR¹, CONR¹CO, CONR¹CR¹ ₂, OCOO, CR¹ ₂OCR¹ ₂, OCR¹₂CO, CR¹ ₂CONR¹, CR¹ ₂CR¹ ₂CR¹ ₂, COCR¹R¹CO, CR¹ ₂NR¹CR¹ ₂, CR¹ ₂SO₂NR¹,CR¹ ₂OCO, or NR¹SO₂NR¹;

where R¹ is hydrogen or a C₁₋₆-alkyl or alkoxy group optionallysubstituted by hydroxy, alkoxy, oxa or oxo (e.g. a polyhydroxyalkyl,formyl, acetyl, hydroxyl, alkoxy or hydroxyalkoxy group), or whereattached to a carbon R¹ may also be a hydroxyl group.

Advantageously, the BG group is not symmetrical. This may be achievedfor exaple by asymmetrical substitution of a symmetrical chain (e.g.N—C—N substituted as NHCONR¹) or by selection of an asymmetric chain(e.g. OCN substituted as OCONR¹). In particular, it is preferred thatthe linker group BG should be polar and also that it should behydrophilic.

Other examples of bridging groups include —NHCO(C₂)_(n) CONH—,—NHCO—(CH₂OCH₂)_(n)—CONH—, —NHCOCH₂(CH₂OCH₂)_(n)CH₂CONH—,—CONHCH₂—(CHOH)_(n)CH₂NHCO—, —NH(Ac)CH₂(CHOH)_(n)CH₂N(Ac)⁻ and—NHCOCH₂CH₂SCH₂CH₂CONH—

where n is an integer between 1 and 6.

This invention further provides new bismuth compounds of formula IIIwhich may be represented as follows:

The R_(A)-R_(C) groups in each of the molecules (for example in IIIa)may be the same or different and typical R_(A)-R_(c) groups aredescribed above.

This invention also provides new bismuth compounds of formula IV whichmay be represented as follows:

The R_(A)-R_(C) groups in each of the above molecules. (for example inIVa) may be the same or different and typical R_(A)-R_(C) groups aredescribed above.

Bismuth compounds of formula V can be represented for example by thefollowing cores:

The bismuth compounds can be prepared from cheap and easily availablebismuth salts. The general synthesis of covalent bismuth compounds iswell described in the above cited reviews on bismuth chemistry.

Thus for example, bismuth compounds of formula I can be synthesized frombismuth (III) chloride as follows:

Bismuth compounds of formula II may for example be synthesized fromtriiodinated X-ray contrast agent derivatives and bismuthoxychloride asfollows:

Bismuth compounds of formula III (with bismuth oxidation number 5) maybe prepared by halogenation of bismuth compounds of formula I followedby a Grignard reaction or using another organometallic reagent such asthe lithium salt as illustrated below:

Bismuth comounds of formula IV may be prepared from the dichlorides asfollows:

For administration to human or animal subjects, the bismuth compoundswill conveniently be formulated together with pharmaceutical orveterinary carriers or excipient. The contrast media of the inventionmay conveniently contain pharmaceutical or veterinary formulation aids,for example stabilizers, antioxidants, osmolality adjusting agents,buffers, pH adjusting agents, colorants, flavours, viscosity adjustingagents and the like. They may be in forms suitable for parenteral orenteral administration, for example, injection or infusion oradministration directly into a body cavity having an external voidanceduct, for exlmpie the gastrointestinal tract, the bladder and theuterus. Thus the media of the invention may be presented in conventionalpharmaceutical administration forms such as tablets. coated tablets,capsules, powders, solutions and suspensions although dispersions inphysiologically acceptable carrier media, e.g. water for injections,will Generally be preferred. Where the medium is formulated forparenteral administrator, the carrier medium incorporating the bismuthcompound is preferably isotonic or somewhat hypertonic. Moreover, mediafor parenteral administration may contain small quantities, e.g. 0.01 to10 mole percent relative at the bismuth compound, of free chelants orweak chelate complexes with physiologically tolerable chelated species(e.g. Ca²⁺); small additions of sodium or calcium salts may alsoadvantageously be made.

For use in X-ray imaging the media of the invention should generallyhave a heavy atom content of 1 millimole/1 to 5 mole/1, preferably 0.1to 2 mole/1. Dosages of from 0.05 to 2.0 mmoles/kg, e.g. 0.5 to 1.5mmoles/kg, will generally be sufficient to provide adequate contrastalthough dosages of 0.8 to 1.2 mmoles/kg will normally be preferred.

For scintigraphy, dosages of the radioactive species will generally besignificantly lower.

Polymers with the bismuth compounds incorporated, for example bound tothe polymer molecules, may be used in medical catheters.

Thus in summary the present invention provides a particularly effectivemeans by which contrast media efficiency may be enhanced by increasingthe relative proportion of molecular volume that is occupied by thecontrast enhancing heavy or paramagnetic metal atom. For X-ray contrastmedia in particular, this also enables higher K-edge value atoms thanthe iodine of the now conventional X-ray contrast media to be utilizedeffectively.

The present invention will now be illustrated further by the followingnon-limiting Examples (all ratios and percentages are by weight and alltemperatures are in degrees Celsius unless otherwise specified):

INTERMEDIATE 1 4-Bromo-1-(2,5-dimethylpyrrolo) benzene

The title compound was prepared according to Bruekelman et al. in J.Chem Soc Perkin Trans I (1984) 2801.

INTERMEDIATE 2 2-(4-Bromophenyl)-4-dimethyl-2-oxazoline

4-Bromobenzoic acid (25.32 g, 126 mmol) and thionyl chloride (54 ml)were stirred in benzene (250 ml) under reflux for 24 hours. The solventwas removed at reduced pressure, and the formed product, 4-bromobenzoylchloride, purified by distillation. Yield 23.30 g (88%), b.p. 82-84° C.(1 mmHg).

4-Bromobenzoyl chloride (20.02 g, 91 mmol) was dissolved indichloromethane (180 ml) and added dropwise to a solution of2-amino-2-methyl-1-propanol (19.20 g, 216 mmol) in dichloromethane (90ml) at ambient temperature. The mixture was stirred for 24 hours atambient temperature, followed by filtration and removal of the solventat reduced pressure. Thionyl chloride (90 ml) was added dropwise and themixture was stirred for 30 minutes at ambient temperature. Excessthionyl chloride was removed at reduced pressure and the residue wasadded to an aqueous HCl-solution (5%, 500 ml). The solution was washedwith ether (2×100 ml) and aqueous NaOH (50%) was added to pH 9. Thebasic solution was extracted with ether (3×100 ml), and the combinedether solution was washed with water (50 ml) and saturated aqueousNaCl-solution. The dried (MgSO₄) ether solution was evaporated and thetitle compound isolated by distillation. Yield 14.14 g (61%), b.p.128-130° C. (1 mm Hg).

¹H NMR (200 MHz, CDCl₃): δ 1.32 (s, 6H), 4.05 (s, 2H), 7.47 (d, 2H),7.75 (d, 2H).

INTERMEDIATE 3 1,2- Bis(dimethylsilyl)benzene

1,2-Dibromobenzene (9.37 g, 40 mmol) in dry tetrahydrofuran (25 ml) wasadded dropwise to a stirred solution of dimethylchlorosilane (7.67 g, 81mmol), magensium (2.00 g, 82 mmol) and one crystal of iodine in drytetrahydrofuran (150 ml). The mixture was heated at reflux for 4 hours,washed with aoueous HCl (100 ml, 2 M) and then with water (3×50 ml). Theorganic solution was dried (MgSO₄), the solvent was evaporated and thetitle product isolated by distillation. Yield 3.87 g (50%), b.p. 54-56°C., Rf: 0.69 (silica, hexane:ether=1:1), MS(EI): 194 (M⁺).

INTERMEDIATE 4 4-Bromo-N,N-(1,2-bis(dimethylsilyl)benzene)aniline

Cesium fluoride (2.19 g, 14.4 mmol) was added to a stirred solution of1,2-bis(dimethylsilyl)-benzene (Intermediate 3) (3.90 g, 20 mmol) in1,3-dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidinone (60 ml) at ambienttemperature. The mixture was stirred for 4 hours at 120° C. The cooledreaction mixture was poured into hexahe/ether (60 ml, 1:1), washed withphosphate buffer at pH7 (3×10 ml) and dried (MgSO₄). The solvent wasevaporated at reduced pressure and the residue was recrystallized frommethanol/ether. Yield: 1.58 g (27%), MS (EI): 361/363.

INTERMEDIATE 5 Dimethyl-t-butylsilylether of 4-bromo-benzyl alcohol

Dimethyl-t-butylsilyl chloride (9.58 g, 65 mmol) was added to a solutionof 4-bromobenzyl alcohol (10.Og, 53 mmol) and imidazole (9.02 g, 133mmol) in dry dimethylformamide (50 ml). The mixture was stirred atambient temperature for 10 hours. Ether (25 ml) and water (25 ml) wasadded and after separation of the phases, the organic phase was washedwith water, dried (MgSO₄) and evaporated. Yield 14.3 g (90%).

EXAMPLE 1 Triphenylbismuth suspension

Human serum albumin (HSA) (3 g) is dissolved in distilled water (150ml). The solution is filtered through a membrane filter with pore size0.45 micron. A filtered solution (0.22 micron) of triphenylbismuth(Fluka) (1.0 g) in 96% ethanol (25.0 ml) is slowly added to the HSAsolution under vigorous stirring over a prolonged period of time. Themicroparticles formed are centrifuged and are washed repeatedly. Theparticles are dispersed in a sterile filtered isotonic 0.9% sodiumchloride/water for injection solution (100 ml) under vigorous stirringuntil a homogeneous suspension is achieved.

EXAMPLE 2 Freeze dried powder comprising tris(4-carboxyphenyl)bismuthtrisodium salt for dissolution in water prior to injection

Tris(4-carboxyphenyl)bismuth is prepared according to Supniewski, J. inRocniki Chem 6 (1926) 97, and the compound (5.0 g) is dissolved in waterby addition of three equivalents of sodium hydroxide. The solution isfilled into a 50 ml vial and freeze dried.

EXAMPLE 3 Dodecafluorodibismatriptycene (C₁₈Bi₂F₁₂) suspension

A filtered solution of dodecafluorodibismatriptycene (0.6 g) intetrahydrofuran (20.0 ml) is slowly added to an aqueous HSA/propyleneglyco solution under vigorous homogenizing.

The microparticles formed are centrifuged and are washed repeatedlybefore the particles are dispersed in a sterile solution of 0.05%polysorbate 80 in saline (5.3 ml).

EXAMPLE 4 Tris (4-hydroxymethylphenyl) bismuthine

Trimethylsilyl chloride (1.9 ml, 15 mmol) was added dropwise to astirred solution of 4-bromobenzyl alcohol (2.0 g, 11 mmol) in toluene(25 ml) and pyridine (2 ml) at 0° C. The stirred mixture was heated toambient temperature during 3 hours. The reaction mixture was filteredand the organic solution evaporated to yield pure 4-bromobenzyltrimethylsilyl ether. The silyl ether can be further purified bydistillation (b.p. 73° C., 0.1 mm Hg). Yield after distillation: 1.49 g(50%)

The above silyl ether (1.49 g, 5.5 mmol) in tetrahydrofuran (10 ml) wasadded dropwise to a stirred mixture of magnesium turnings (0.13 g, 5.5mmol) in tetrahydrofuran (20 ml) containing a few crystals of iodine.The mixture was heated at reflux until all magnesium was dissolved.Bismuth (III) bromide (0.62 g, 1.4 mmol) was gradually added and thereaction mixture was heated to reflux for 2 hours. The cooled mixturewas filtered through a plug of celite followed by addition of drytetrabutylammonium fluoride (1.46 g, 5.6 mmol) at 0° C. The stirredreaction mixture was heated to room temperature during 2 hours followedby evaporation of the solvent. Chloroform (20 ml) and water (10 ml) wereadded to the residue and the title compound precipitated out as a whitecrystalline material. The product was washed with chloroform. Yield 0.22g (30%) m.p.>300° C.

¹H NMR (200 MHz, DMSO-d₆): δ 4.47 (d, 2H), 5.15 (t, 1H) 7.3(d, 2H) and7.70 (d, 2H).

EXAMPLE 5 Tris(4-hydroxyphenyl)bismuthine

Trimethylsilyl chloride (11 ml, 87 mmol) was added dropwise to a stirredsolution of 4-bromophenol (10.0 g, 58 mmol) in toluene (25 ml) andpyridine (20 ml) at a 0° C. The stirred mixture was heated to ambienttemperature during 3 hours. The reaction mixture was filtered and theorganic solution evatorated to yield pure 4-bromophenyl trimethylsilylether. The silyl ether can be further purified by distillation (b.p.122° C., 20 mmHg). Yield after distillation: 13.70 g (75%).

The above silyl ether (13.70 g 43 mmol) in tetrahydrofuran (25 ml) wasadded dropwise to a stirred mixture of magnesium turnings (1.06 g, 43mmol) in tetrahydrofuran (25 ml) containing a few crystals of iodine.The mixture was heated at reflux until all magnesium was dissolved.Bismuth (III) bromide (4.82 g, 11 mmol) was gradually added and thereaction mixture was heated to reflux for 2-3 hours. The cooled mixturewas filtered through a plug of celite followed by addition of drytetrabutylammonium fluoride (11.5 g, 44 mmol) at 0° C. The stirredreaction mixture was heated to room temperature during 2 hours followedby evaporation of the solvent. Chloroform (20 ml) and water (10 ml) wereadded to the residue and the title compound precipitated out as a whitecrystalline material. The product was washed with cold chloroform. Yield1.59 g (22.5%) mp>300° C.

¹H NMR (200 MHz, DMSO) 6.87 (d, 2H), 8.20 (d, 2H), 9.35 (s, 1H).

EXAMPLE 6 Tris(4-(2,5-dimethylpyrrolo)phenyl) bismuthine

n-Butyllithium in hexane (13.5 ml, 1.5 M, 20 mmol) was added dropwise toa stirred solution of 4-bromo-1-(2,5-dimethylpyrrolo) benzene(Intermediate 1) (5.0 g, 20 mmol) in tetrahydrofuran (75 ml) at −78° C.under an atmosphere of dry argon. After 10 minutes, the solution washeated to −30° C. followed by dropwise addition of a solution of bismuth(III) bromide (2.15 g) in tetrahydrofuran (10 ml). The mixture wasstirred for 2.5 hours during heating to room temperature, filtered andthe organic solution was evaporated. The residue was recrystallized frombenzene. Yield 2.40 g (70%), white crystalline material, m.p.>300° C.(decomposed).

¹H NMR (300 MHz, CDCl₃): δ 2.06 (s, 18H), 5.91 (s, 6H), 7.28 (d, 6H),7.88 (d, 6H).

EXAMPLE 7 Tris (4-(4,4-dimethyl-2-oxazoline) bismuthine

2-(4-Bromophenyl)-4-dimethyl-2-oxazoline (Intermediate 2) (13.93 g, 55mmol) dissolved in dry tetrahydrofuran (75 ml) was added dropwise to asuspension of magnesium turnings (1.34 g, 55 mmol) and one crystal ofiodine in tetrahydrofuran (100 ml). The reaction mixture was stirreduntil all the magnesium turnings dissolved. The mixture was stirred foranother hour at ambient temperature followed by dropwise addition ofbismuth (III) bromide (6.34 g, 13.8 mmol) in dry tetrahydrofuran (10ml). The reaction mixture was stirred at 55° C. under an argonatmosphere overnight, followed by filtration through a plug of celiteand added to ice-water (200 ml). The mixture was extracted with ethylacetate (3×100 ml), the combined organic phase was dried (MgSO₄),evaporated and the residual material subjected to flash chromatographyon silica using ethyl acetate: yield 7.48 g (72%), Rf: 0.25 (silica,ethyl acetate), white crystalline material m.p. 233-234° C.

¹H NMR (300 MHz, CD₃OD). δ 1.34 (s,18H), 4.14 (s, 6H), 7.80 (d, 6H),7.87 (d, 6H).

EXAMPLE 8 Tris (4-bromophenyl) bismuthine

n-Butyllithium in heptane (2.7 M, 9.25 ml, 50 mmol) was added dropwiseto a solution of 1,4-dibromobenzene (5.90 g, 50 mmol) in drytetrahydrofuran (250 ml) under an atmosphere of dry argon at −78° C. Themixture was stirred for 1 hour at −78° C. A solution of bismuth (III)bromide (2.92 g, 12.5 mmol) in dry tetrahydrofuran (20 ml) was slowlyadded and the mixture was stirred overnight. After filtration through aplug of celite, the solvent was removed at reduced pressure, and theresidue subjected to flash chromatography on silica gel usingdichloromethane hexane (20:80); yield: 3.05 g (72%), Rf: 0.40 (silica,dichloromethane: hexane (20.80).

¹³C NMR (200MHz, CDCl₃): δ 122.89, 133.78, 139.02 and 153.30.

EXAMPLE 9 Tris (4-ethyloxycarbonylphenyl) bismuthine

n-Butylithium in heptane (4.89 ml, 2.7 M, 13.2 mmol) was dropwise addedto a stirred solution of tris (4-bromophenyl) bismuthine (from Example8) (2.71 g, 4 mmol) in dry tetrahydrofuran (40 ml) under an atmosphereof argon at −78° C. The mixture was stirred overnight followed byfiltration through a plug of celite and poured into water (50 ml). Themixture was extracted with ethyl acetate (3×50 ml), the combined organicsolution was dried (MgSO₄) and the solvent evaporated at reducedpressure. The white powder was purified by flash chromatography to yield1.03 g (52%) of the title compound as a white crystalline powder.

¹H NMR (200 MNz, CDCl₃). δ 1.36 (t, 9H), 4.35 (q, 6H) 7.54 (d, 6H) and7.88 (d, 6H).

EXAMPLE 10 Tris (4-hydroxyphnyl) bismutbine dihromide

Bromine (3 mmol, 0.16 ml) was added dropwise to a stirred mixture oftris (4-hydroxyphenyl) bismuthine (Example 5) (1.5 g, 3 mmol) inmethanol (25 ml) at 0° C. The mixture was stirred for 1 hour at ambienttemperature. The solvent was removed under reduced pressure. The residuewas washed with chloroform and the title compound isolated as a whitecrystalline material. Yield: 1.20 g (62%).

¹H NMR (300 MHz, DMSO-d₆) 7.09 (d, 2H), 9.00 (d, 2H), 9.43 (s, 1H).

EXAMPLE 11 Tris (3,5-diiodo-4-hydroxy phenyl) bismuthine dibromide

Benzyltrimethylammonium dichloroiodate (prepared according to Kajigaeshiet al. in Chem Lett. (1987) 2109 (3.49 g, 10 mmol) and sodium hydrogencarbonate were added to a solution of tris (4-hydroxyphenyl) bismuthinedibromide (Example 10) (1.0 g, 1.54 mmol) in a mixture ofdichloromethane and methanol (30 ml, 2:1) at ambient temperature. Themixture was stirred for 24 hours at ambient temperature. Ether (100 ml)was added and the organic solution with precipitate was washed withwater, and the title compound was isolated as a white crystallinepowder. Yield 0.43 g (20%). MS showed peak

m/e 209 (Bi) ¹H NMR (300 MHz), DMSO-d₆) 7.53 (s)

EXAMPLE 12 BiDTPA-aminoethyl dextran for X-ray blood pool imaging

Bisanhydride of DTAA (3.25g) (prepared from DTPA according to Eckelmanin J. Pharm. Sci. 64 (1975) 704) was gradually added to a solution ofaminoethyl dextran (MW 80,000, 5.0 g) in dry dimethylsulphoxide (400 ml)at ambient temperature. The mixture was stirred for 20 hours at the sametemperature followed by addition of water (700 ml). The pH value wasadjusted to 5.5, a solution of bismuth (III) nitrate pentahydrate (4.85g, 10 mmol) in water (50 ml) was added, the pH value was adjusted to 4.8and the solution was dialyzed against 0.9 ak (w/v) NaCl for one week.The aqueous solution was evaporated and the product was dried in vacuumat 50° C. Yield: 7.2 g white solid material containing 6.0% bismuth.

EXAMPLE 13 Bismuth (III) chelate of18-[{3-(2-carboxybutyl)-2,4,6-trifodophenyl}amino]-3,6,9-tris(carboxymethyl)-11,18-dioxo-2,6,12-tetraazaoctadecanoicacid

The chelating agent above (prepared according to WO94/27644)(20.3 g,0.02 mol) is dissolved in water (800 ml). Freshly precipitated bismuthhydroxide (0.02 mol) (prepared from bismuth nitrate pentahydrate andsobium hydroxide) is added and the mixture is stirred at 100° C. for 24hours. The solvent is evaporated at reduced pressure and the titlecompound is isolated as a white crystalline material.

EXAMPLE 14 Tris (2,4,6trimethylphenyl)bismuthine

The compound was prepared according to Matano et al. in Bull Chem Soc.Jpn, 65 3504 (1992). Yield: 771%

EXAMPLE 15 Tris(2,4,6trimethylphenyl)bismuthine dichloride

Thionyl chloride (1.48 g, 11 mmol) was added to a solution oftris(2,4,6-trimethylphenyl)bismuthine (Example 14) (5.66 g, 10 mmol) inhexane (100 ml) at ambient temperature. The mixture was stirred for onehour and the precipitated product was isolated and recrystalized fromethanol. Yield: 5.70 g (90%).

¹H NMR (300 MHz, CDCl³): 2.32 (9H), 2.74 (18H), 7.16 (6H).

EXAMPLE 16 Triphenylbismuthine difluoride

The compound was prepared according to Challenger and Wilkinson in J.Chem Soc. 121: 91 (1922). Yield: 75%.

EXAMPLE 17 Tris(2,6-dimethylphenyl)bismuthine

2-Bromo-m-xylene (9.25 g, 50 mmol) in ether (15 ml) was added dropwiseto a stirred suspension of magnesium (1.22 g, 50 mmol) and some crystalsof iodine in ether (20 ml) at 0° C. When the Grignard reagent was formed(4 hours), the mixture was stirred at ambient temperature for one hour.Bismuth chloride (3.15 g, 10 mmol) was added and the mixture was stirredfor 10 hours. The reaction mixture was poured into sat,rated ammoniumchloride solution an extracted with ether (3×20 ml) The combined organicphase was cried (MgSO₄) and the solvent evaporated at reduced pressure.The title compound was recrystallised from ethanol. White solid, yield:1.81 g (35%).

¹³C NMR (200 MHz CDCl₃) δ 28.53, 127.17, 127.52, 145.05, 158.42.

EXAMPLE 18 Tris(4-aminophenyl)bismuthine protected with1,2-bis(dimethylsilyl) benzene

n-Butyllithium in hexane (2.50 ml, 1.6M, 4 mmol) was added dropwise to astirred solution of 4-bromo-N,N-(1,2-bis(dimethylsilyl)benzene)aniline(Intermediate 4)(1.45 g, 4 mmol) in tetrahydrofuran at −78° C. Themixture was stirred for 1 hour, a solution of bismuth bromide (0.45 g, 1mmol) in tetrahydrofuran (10 ml) was added and the reaction mixture wasstirred overnight. The mixture was poured into phosphate buffer pH 7 (50ml), the acueous phase was extracted with chloroform (3×50 ml), thecombined organic phases (tetrahydrofuran and chloroform) was dried(MgSO₄) and the solvents evaporated at reduced pressure. The product wasrecrystallised from hexane/ether and isolated as a white crystallinematerial. Yield: 0.60 g (57%). Anal.: C: 54.51%, H: 5.79%, H: 4.09%(Calculated: C: 54.57%, H: 5.72%, N: 3.98%)

EXAMPLE 19 Bis(4-hydromethylnhenyl)bismuth bromide as bistrimethyl-t-butyl ether

Bismuth tribromide (0.9 g, 2.1 mmol) was added to a solution ofsilylether (Intermediate 5) (5.62 g, 6.4 mmol) in tetrahydrofuran (25ml) at ambient temperature. The stirred mixture was refluxed overnight,the solvent was evaporated at reduced pressure and the title compoundwas purified on flash chromatography (silica, hexane:ethyl-acetate 8:1).Yield 1.59 g (35%).

¹H NMR (200 MHz, CDCl₃): δ 0.17 (s, 12H), 0.99 (s, 18H) 4.80 (s, 4H),7.65 (d, 4H), 8.20 (d, 4H)

EXAMPLE 20 p-Phenylene-bis (di(4-hydoxymethylelylbismuthin) asdimethyl-t-butylsilyl ether

n-Butyllithium in hexane (1.51 ml, 1.6M, 2.4 mmol) was added dropwise toa stirred solution of 1,4-dibromo-benzene (0.26 g, 1.1 mmol) intetrahydrofuran (15 ml) at −-78° C. The mixture was stirred for 1.5hour, the silyl ether from Example 19 (1.59 g, 2.2 mmol) intetrahydrofuran (10 ml) was added and the mixture was warmed up toreflux temperature during one hour. After 10 hours reflux the mixturewas extracted with aqueous sodium chloride solution (40 ml, 5%) andextracted with water (2×10 ml). The dried (MgSO₄) organic solution wasevaporated and the title compound purified by flash chronatography(silica, hexane:ethylacetate 8:2). Yield: 0.67 g (22%).

¹H NMR (200 MHz, CDCl₃) δ 0.19 (s, 18H), 1.03 (s, 27H), 4.81 (s, 6H),7.42 (d, 6H), 7.52 (q, 4H), 7.78 (d, 6H).

EXAMPLE 21 Preparation of tetrabenzylalcohol from Examnle 20

The silylether (from Example 20) is cleaved with tetrabutylammoniumfluoride in tetrahydrofuran.

EXAMPLE 22 Preparation of tris (4-aminophenyl)bisrnuthine from Example18

The silyl-derivative (from Example 18) is cleaved withtetrabutylammonium fluoride according to standard methods in organicchemistry.

EXAMPLE 23 Activity of bismuth compounds against Helicobarter pylori

Various bismuth compounds were tested in different concentrationsagainst Helicobacter pylori on agar plates. Minimal InhibitoryConcentrations (MIC—values) are given in mg substance per litre.

Substance Example No. MIC - value Tris(2,4,6-trimethylphenyl)- 15 ≦0.25bismuthine chloride Tris(2,4,6-trimethylphenyl)- 14 ≦0.25 bismuthineTriphenylbismuthine 16 8 difluoride Tris(2,6-dimethylphenyl)- 17 4bismuthine Bismuth subsalicylate — 4 Bismuth subnitrate — 32

What is claimed is:
 1. A method of treating a gastrointestinal disorderin a human or non-human animal body which method comprises administeringto said body a physiologically tolerable dose of a compound selectedfrom formulae I-IV

where the groups R₁-R₅ may be the same or different and are groupsforming a hydrolytically stable bond to bismuth and X is O, S or NR₆where R₆ is lower alkyl, substituted lower alkyl or an aryl group.
 2. Amethod as claimed in claim 1 wherein R₁-R₅ are selected from arylgroups.
 3. A method as claimed in claim 2 wherein R₁-R₅ are optionallysubstituted benzene.
 4. A method as claimed in claim 2 wherein R₁-R₅ areoptionally substituted pyridine.
 5. A method as claimed in claim 1wherein said compound is triphenyl bismuth, tris(4-carboxyphenyl)bismuth, tris(4-hydroxymethylphenyl) bismuthine, tris(4-hydroxyphenyl)bismuthine, tris(4-(2,5-dimethylpyrrolo) phenyl) bismuthine,tris(4-(4,4-dimethyl-2-oxazoline)phenyl) bismuthine, tris(4-bromophenyl)bismuthine, tris(4-ethyloxycarbonylphenyl) bismuthine,tris(4-hydroxyphenyl) bismuthine dibromide, tris(2,4,6-trimethylphenyl)bismuthine, tris(2,4,6-trimethylphenyl) bismuthine dichloride, triphenylbismuthine difluoride, or tris(2,6-dimethylphenyl) bismuthine.
 6. Amethod as claims in claim 1 wherein the disorder is caused byHeliobacter pylori.